We utilized two recently developed transgenic in vivo mutagenicity assays that are based on the phage l-derived shuttle vector, l-LIZ, and the plasmid-derived shuttle vector, placZ, to study the role of B-cell mutagenesis in the pathogenesis of inflammation-induced peritoneal plasmacytomas in genetically susceptible BALB/c mice. The studies include (a) the mutagenicity of the inflammatory granuloma, which is the tissue site of plasmacytoma development, (b) the genetic control of B-cell mutagenesis in relation to the genetic susceptibility/resistance to plasma cell tumor development, and (c) the widely presumed but poorly documented requirement of general (oxidative) B-cell mutagenesis for plasmacytoma development. To devise an experimental system that is conducive for genetic studies on mouse plasmacytomagenesis, Klaus Felix decided to backcross the l-LIZ and placZ shuttle vectors onto plasmacytoma-susceptible BALB/cAnPt mice and plasmacytoma-resistant DBA/2N mice. He has completed the backcross; i. e., genetically pure BALB/cAnPt mice and DBA/2N mice congenic for the two shuttle vectors are now available. Using the BALB/cAnPt.l-LIZ mouse in his most recently published experiment, Klaus Felix found that elevated mutant rates persist for a long time in the spleen of mice exposed to sustained oxidative stress (Cancer Res. 58, 1616-1619, 1998).Lynne Rockwood, who joined the project in FY ?99, has initiated studies on the relationship between general cellular metabolism and mutation control. Specifically, she is using the partial loss of function mutant of a general house-keeping gene, glucose 6-phosphate dehydrogenase (G6PD), to associate the ability of a B cell to supply reducing equivalents in form of NADPH<sub>2</sub> with elevated spontaneous mutagenesis in vivo. Her preliminary observations suggest a previously unrecognized link between genomic instability (deletion mutations), increases in mean mutant levels (spleen and brain), and genetic deficiencies in metabolic pathways that were previously not implied maintaining genetic stabililty. Ming Qian, who also joined the program recently, has decided to explore the hypothesis that the deregulated expression of the proto-oncogene c-myc, a hallmark of BALB/c plasmacytomas, may result in elevated mutagenesis and genomic instability. He is currently developing methods to associated the inducible expression of c-myc with mutagenesis that can be assessed with the transgenic shuttle vectors, l-LIZ and placZ. - B lymphocytes, plasmacytoma, mutagenesis in vivo, oxidative DNA damage, - Neither Human Subjects nor Human Tissues